Human genetics influences microbiome composition involved in asthma exacerbations despite inhaled corticosteroid treatment
Authors: Javier Perez-Garcia, Antonio Espuela-Ortiz, José M. Hernández-Pérez, Ruperto González-Pérez, Paloma Poza-Guedes, Elena Martin-Gonzalez, Celeste Eng, Olaia Sardón-Prado, Elena Mederos-Luis, Paula Corcuera-Elosegui, Inmaculada Sánchez-Machín, Javier Korta-Murua, Jesús Villar, Esteban G. Burchard, Fabian Lorenzo-Diaz, Maria Pino-Yanes
Journal: Journal of Allergy and Clinical Immunology (2023)

BackgroundThe upper-airway microbiome is involved in asthma exacerbations despite inhaled corticosteroid (ICS) treatment. Although human genetics regulates microbiome composition, its influence on asthma-related airway bacteria remains unknown.ObjectiveWe sought to identify genes and biological pathways regulating airway-microbiome traits involved in asthma exacerbations and ICS response.MethodsSaliva, nasal, and pharyngeal samples from 257 European patients with asthma were analyzed. The association of 6,296,951 genetic variants with exacerbation-related microbiome traits despite ICS treatment was tested through microbiome genome-wide association studies. Variants with 1 × 10−4 < P < 1 × 10−6 were examined in gene-set enrichment analyses. Significant results were sought for replication in 114 African American and 158 Latino children with and without asthma. ICS-response–associated single nucleotide polymorphisms reported in the literature were evaluated as microbiome quantitative trait loci. Multiple comparisons were adjusted by the false discovery rate.ResultsGenes associated with exacerbation-related airway-microbiome traits were enriched in asthma comorbidities development (ie, reflux esophagitis, obesity, and smoking), and were likely regulated by trichostatin A and the nuclear factor-κB, the glucocorticosteroid receptor, and CCAAT/enhancer-binding protein transcription factors (7.8 × 10−13 ≤ false discovery rate ≤ 0.022). Enrichment in smoking, trichostatin A, nuclear factor-κB, and glucocorticosteroid receptor were replicated in the saliva samples from diverse populations (4.42 × 10−9 ≤ P ≤ .008). The ICS-response–associated single nucleotide polymorphisms rs5995653 (APOBEC3B-APOBEC3C), rs6467778 (TRIM24), and rs5752429 (TPST2) were identified as microbiome quantitative trait loci of Streptococcus, Tannerella, and Campylobacter in the upper airway (0.027 ≤ false discovery rate ≤ 0.050).ConclusionsGenes associated with asthma exacerbation–related microbiome traits might influence asthma comorbidities. We reinforced the therapeutic interest of trichostatin A, nuclear factor-κB, the glucocorticosteroid receptor, and CCAAT/enhancer-binding protein in asthma exacerbations. The upper-airway microbiome is involved in asthma exacerbations despite inhaled corticosteroid (ICS) treatment. Although human genetics regulates microbiome composition, its influence on asthma-related airway bacteria remains unknown. We sought to identify genes and biological pathways regulating airway-microbiome traits involved in asthma exacerbations and ICS response. Saliva, nasal, and pharyngeal samples from 257 European patients with asthma were analyzed. The association of 6,296,951 genetic variants with exacerbation-related microbiome traits despite ICS treatment was tested through microbiome genome-wide association studies. Variants with 1 × 10−4 < P < 1 × 10−6 were examined in gene-set enrichment analyses. Significant results were sought for replication in 114 African American and 158 Latino children with and without asthma. ICS-response–associated single nucleotide polymorphisms reported in the literature were evaluated as microbiome quantitative trait loci. Multiple comparisons were adjusted by the false discovery rate. Genes associated with exacerbation-related airway-microbiome traits were enriched in asthma comorbidities development (ie, reflux esophagitis, obesity, and smoking), and were likely regulated by trichostatin A and the nuclear factor-κB, the glucocorticosteroid receptor, and CCAAT/enhancer-binding protein transcription factors (7.8 × 10−13 ≤ false discovery rate ≤ 0.022). Enrichment in smoking, trichostatin A, nuclear factor-κB, and glucocorticosteroid receptor were replicated in the saliva samples from diverse populations (4.42 × 10−9 ≤ P ≤ .008). The ICS-response–associated single nucleotide polymorphisms rs5995653 (APOBEC3B-APOBEC3C), rs6467778 (TRIM24), and rs5752429 (TPST2) were identified as microbiome quantitative trait loci of Streptococcus, Tannerella, and Campylobacter in the upper airway (0.027 ≤ false discovery rate ≤ 0.050). Genes associated with asthma exacerbation–related microbiome traits might influence asthma comorbidities. We reinforced the therapeutic interest of trichostatin A, nuclear factor-κB, the glucocorticosteroid receptor, and CCAAT/enhancer-binding protein in asthma exacerbations.